Brian P. Vickery, MD

Disclosures

Curr Opin Allergy Clin Immunol. 2012;12(3):278-282. 

In This Article

Conventional Pilot Studies

Studies of the treatment of food-allergic patients with a form of OIT were published at least as early as 1930[11] and continued throughout the 20th century. These early attempts at oral therapy were based on the concept of gradually increasing allergen administration in the treatment of allergic rhinoconjunctivitis, popularized by subcutaneous injection immunotherapy. They utilized primarily crude extracts of fresh food and did not include mechanistic studies. In the 2000s, several investigators, primarily although not exclusively working in Europe, published small pilot studies that established the feasibility of egg OIT.[12–15] This included a trial that used interferon-g as an adjuvant.[16] In one of the first controlled studies of OIT, Patriarca et al.[13] showed safety and proofof-concept, documenting gradual clinical, and immunologic changes in most treated patients but not untreated standard-care controls. In this study of 59 adults and children with milk, egg, fish, and other food allergies, the control group consisted of 16 patients who refused to participate in active treatment; such a control group may have important reasons for not participating in active treatment, and thus may not be as generalizable as those randomly assigned allergen avoidance. Fifteen egg-allergic patients were treated with a liquid extract of raw whole egg, and doses were gradually escalated to the equivalent of one full egg per day over the course of approximately 5 months, at which time they were instructed to eat one whole egg at least twice per week as a maintenance therapy. Desensitization was considered successful by virtue of regular egg ingestion without evident clinical symptoms. Double-blind, placebo-controlled food challenges (DBPCFC) were performed at baseline to confirm the diagnosis, but there was no food challenge conducted after treatment to formally assess eliciting dose thresholds. Eleven of 15 (73%) completed the protocol and were considered successful. The ages of these patients and their egg-specific immunologic data were not reported in this study. Across the active treatment group as a whole, allergen-specific IgE declined and was accompanied by a rise in allergen-specific immunoglobulin G (IgG)4, similarly to other immunotherapy studies. Among the control group, there were no changes in skin pricktests or in-vitro testsandafter18months, the DBPCFCs remained positive in all controls. Fiftyone percentage of treated patients developed allergic side effects that responded well to standard antihistamines or cromolyn.

In one of the first US studies of egg OIT, Buchanan et al.[17] enrolled seven children aged 14 months to 7 years in an open-label clinical trial in a large referral center. After 24 months of maintenance treatment, in which all patients were treated with 300mg of daily egg white powder mixed into a vehicle food, four of seven (57%) patients passed an oral food challenge without any symptoms while on treatment and were considered desensitized. However, thereafter egg OIT was stopped for 3 months to assess whether the desensitization effect would persist, and two of four (50%) regained clinical sensitivity during a followup food challenge, suggesting that the state of desensitization was transient. No changes in egg IgE levels were observed, but egg IgG levels increased. Subsequent patients in the same center were enrolled in a modified protocol, reported by Vickery et al. [18•] In this follow-up study, the maintenance dose of egg OIT was individualized based on the patient's egg white IgE level, and serial dose escalations were incorporated in an attempt to decrease the IgE level below 2 kUA/l to increase efficacy. The result of using such an approach was that patients were treated with higher daily dosages (median 2400mg) and for much longer (median 33 months) than in the study of Buchanan et al. As a result, six of six (100%) patients, including three patients whose egg white IgE remained more than 4kUA/l despite dose escalation, passed a DBPCFC 1 month after stopping OIT were considered tolerant and were advised to consume egg products ad libitum. Skin prick tests and specific IgE levels to egg white decreased, and there were no changes in egg-specific cytokines or CD4þ CD25þ T cell numbers. Although both of these studies from the same center demonstrated that some OIT-treated patients will develop tolerance, as evidenced by passage of a DBPCFC after discontinuing OIT, it is not possible to conclude that the OIT caused the tolerance to occur.

None of these studies incorporated randomization techniques or a placebo control, which are key limitations in the study of a disease for which spontaneous improvement is the expected course. As a result, these studies can be regarded as proof-ofconcept (e.g. OIT can be safely and feasibly performed and has immunomodulatory properties), but they do not provide definitive evidence of the efficacy of egg OIT. These studies suggest that short trials with relatively low-maintenance doses may only provide evidence of transient desensitization, whereas true tolerance, if it does occur with OIT, may require longer treatment with higher dose therapy. This concept is consistent with the similar results of two trials of milk OIT, in which partial efficacy in desensitization was demonstrated after a short randomized placebo-controlled trial,[19] followed by consolidation of the effect during a longer, higher dose open-label extension.[20]

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